Spiro(3,3)heptane amino acids

ABSTRACT

NOVEL SPIRO(3.3)HEPTANE AMINO ACIDS AND THEIR DERIVATIVES ARE DISCLOSED AND THEIR METHOD OF PREPARATION IS DESCRIBED.

United States Patent 3,748,354 SPIRO[3,3]HEPTANE AMINO ACIDS Larry J.Loeiiier, Bethesda, Md, assignor to Merck & Co., Inc, Rahway, NJ.

No Drawing. Original application Apr. 1, 1970, Ser. No. 24,885, nowPatent No. 3,666,790. Divided and this application June 16, 1971, Ser.No. 153,859

Int. Cl. C07c 101/04, 101/14, 101/18 US. Cl. 260-514 G 3 Claims ABSTRACTOF THE DISCLOSURE Novel spiro[3.3]heptane amino acids and theirderivatives are disclosed and their method of preparation is described.

H R 000 R;

where:

R, is hydrogen or alkyl (preferably lower alkyl from about 1-5 carbonatoms); and R is COOR; CONH CN; CH NH where R is alkyl (preferably loweralkyl from about 1-5 carbon atoms), with the proviso that R, is notalkyl when R is COOR.

Included within the scopeof this invention are the hydrates and thesalts of the amine and the carboxylic acid groups of the compounds ofthe above formula. The hydrates and salts do not differ from thecompounds themselves but rather provide a convenient solubility factor.Such salts would include the inorganic and organic acid addition saltsof the amines such as those prepared from hydrochloric acid, sulfuricacid, phosphoric acid, methane-sulfonic acid, propionic acid, etc. Alsoincluded are the alkali; alkaline earth or aluminum metal salts of thecarboxylic acid.

The more preferred compounds of this invention are those described bythe formula:

where n is O or 1 and R is described above.

The most preferred compounds of this invention are6-aminospir0[3.3]heptane-2-carboxylic acid and 6-aminomethylspiro 3 .3heptane-Z-carboxylic acid.

Polycarboxamides are well known in the art and have received widespreaduse due to the excellent chemical and physical properties they exhibitas nylons.

Demand for new polymers continues to increase, and amino acid compoundswhich will form polycarboxamide polymers with diiferent chemical andphysical properties are continually sought after.

The amino acid products prepared in accordance with the presentinvention can be easily converted to polyamides by methods known in theart. Such polyamide synthesis is disclosed in such as US. Pats. Nos.2,071,250; 2,071,253; 2,252,555; 2,768,994; 2,130,523; 2,252,557;

"ice

3,027,352; 2,130,948; 2,374,137; 3,028,365; 2,190,770; 2,385,890.Polyamides are particularly useful for modifying the properties of otherpolyamides by the replacement of a portion of a polymer molecule with aportion of a different polyamide such as replacement of a portion of anacid of the US. Pat. No. 3,081,334 with one or more of the acids whichcan be prepared by the present invention.

The compounds of the present invention may also be useful asplasticizers for natural and synthetic resins and can be converted intopharmaceutical products.

The compounds of the present invention may be prepared by the followingprocesses.

Spiro[3.3]heptane 2,6 dicarboxylic acid may be diesterified under normalconditions (preferably diazomethane). The resulting alkylspiro[3.3]heptane-'2,6-di carboxylate (VIII) is then hydrolyzed with oneequivalent of alkali to afford the alkyl hydrogen spiro[3.3]heptane-2,6-dicarboxylate (VII). Successive treatment of the alkyl hydrogenspiro[3.3]heptane-2,6dicarboxylate (VII) with triethylamine, ethylchlorocarbonte at 10 and anhydrous ammonia results in alkyl 6-carbamoylspiro[3.3] heptane-Z-carboxylate (VI).

Treatment of alkyl 6-carbamyl spiro[3.3]heptane-2- carboxylate (VI) withbromine and sodium alkoxide in alcohol gives the urethane derivative (V)which on acid hydrolysis yields 6-aminospiro[3.3]heptane-Z-carboxylicacid (IV).

Dehydration of alkyl 6-carbamoyl spiro[3.3]heptane- 2-carboxylate withphosphorus oxychloride in ethylene dichloride results in alkyl 6-cyanospiro[3.3]heptane-2- carboxylate (III). This is then saponified with anexcess of alkali, followed by acidification to give 6-cyanospiro[3.3]heptane-2-carboxylic acid (II) which can then be catalyticallyreduced to the desired 6-aminomethylspiro [3.3]heptane-2-carboxylic acid(I) The following structural formulas illustrate the preparation of thecompounds of this invention:

H H XXX ROOC OOOR ROOO COOH ROOC CONH, 1

1! H /H H H R000 CN R000 NHCOOR III V N NH;

where R is alkyl. The preparation of dimethyl spiro[3.3]heptane-2;6-dicarboxylate may be found in J. Org. Chem: 26, 54 (1961).

The following examples illustrate this invention and are not intended tobe a limitation of it.

EXAMPLE 1 fi-aminomethylspiro 3 .3 ]heptane-2-carb oxylic acid HOOG CHNH diazomethane. The reaction mixture is stirred for 10 min- 7 utes,then extracted three times wtih 25 ml. portions of sodium bicarbonatesolution and dried over magnesium sulfate. The ether solution is thenevaporated to dryness to obtain dimethylspiro[3.3]heptane-Z,6-dicarboxylate.

(B) Methyl hydrogen spiro[3.3]heptane-2,6-dicarboxylate: 4. 67 g. (22.0mmoles) of dimethyl ester from step A is added to a cooled solution ofsodium hydroxide [0.51 g. (22.0 mmoles) sodium spheres dissolved in 25ml. of methanol], followed by cautious addition of 1.25 ml. water undera nitrogen atmosphere]. The reaction is then refluxed for 18 hours andthen evaporated to dryness in vacuo at -40 C. Water (25 ml.) is addedand the mixture extracted three times with 20 ml. portions of ether. Thewater layer is cooled, acidified with 5 ml. of '6 N HCl and the oilwhich separates is extracted four times with 25 ml. portions ofchloroform. The chloroform is then washed with water, dried overmagnesium sulfate and evaporated to dryness. The resulting material ischromatographed on silica gel using chloroform as an eluant and theproduct thereby eluted is recrystallized from hexane to obtain methylhydrogen spiro[3.3]heptane-2,6-dicarboxylate (M.P. 53-55" C.).

(C) Methyl 6-carbamoylspiro[3.3]heptane-2-carboxylate: 1.58 g. (8.0mmoles) of monoacid from step B is dissolved in 25 ml. of drychloroform. This is then cooled in an ice-salt bath to -10 C. and tothis is added 0.81 g. (8.0 mmoles) of triethylamine dissolved in 10 ml.of chloroform and followed by 0.87 g. (8.0 mmoles) of ethylchloroforrnate dissolved in 10 ml. of chloroform over a 5 minute period,keeping the temperature below --5 C. The reaction mixture is thenstirred for 15 minutes at 5 C. With continued cooling ammonia gas isbubbled into the reaction mixture for 10 minutes. The reaction mixtureis then allowed to warm to room temperature and stirred for 20 hours.The suspension is shaken with 20 ml. of cold water and the chloroformlayer is extracted three times with 10 ml. portions of 0.1 Nhydrochloric acid, three times with 10 ml. portions of saturated sodiumbicarbonate solution and three times with 10 ml. portions of water. Thechloroform is then dried over magnesium sulfate and evaporated todryness in vacuo at 40 C., resulting in a solid which is recrystallizedfrom benzene to obtain methyl 6-carbamoyl spiro[3.3]heptane 2carboxylate (M.P. 148.5- 150 C.).

(D) Methyl 6-cyanospiro[3.3Iheptane-Z-carboxylate: 0.78 g. (395 mmoles)of the amide-ester from step C is dissolved in 20 ml. of warm1,2-dichloroethane and 1.70 ml. of phosphorus oxychloride is added andthe mixture refluxed for 20 minutes. Most of the phosphorus oxychlorideis then distilled off at 15 mm./90-100 C. and the reaction residuepoured into 20 ml. of ice cold saturated sodium bicarbonate. The oilthat separates is extracted four times with 20 ml. portions of n-pentaneand the combined extracts are then washed with sodium bicarbonatesolution and dried over magnesium sulfate. The pentane solution is thenevaporated to dryness to obtain methylfi-cyanospiro[3.31heptane-2-carboxylate.

(E) -6-cyanospiro[3.3]heptane-2-carboxylic acid: 410 mg. (2.29 mmoles)of the nitrile-ester from step D is dissolved in 10 ml. of ethanol and1.38 ml. of 2 N sodium hydroxide (20% excess) solution is added. Thereaction mixture is refluxed for two hours, then allowed to stir at roomtemperature for 15 hours. The reaction mixture is then evaporated todryness, the residue treated with water and extracted with ether. Theaqueous layer is then acidified with 1 ml. of 6 N hydrochloric acid andthe oil that separates is extracted five times with ether. The ether isdried over magnesium sulfate and evaporated to dryness to obtain6-cyanospiro[3.3]heptane-Z-carboxylic acid (M.P. 98-101 C.).

(F) G-aminomethylspiro[3.3]heptane 2 carboxylic acid: 250 mg. (1.51mmoles) of the nitrile-acid from step E is dissolved in 20 ml. ofabsolute ethanol. To this is added 0.50 ml. of 6 N HCl and 100 mg. ofplatinum oxide. The mixture is then hydrogenated at 30 lbs./in. and roomtemperature for 1 hour, after which the catalyst is removed byfiltration and the filtrate allowed to evaporate to dryness. The residueis then treated wtih 10 ml. of 3 N HCl and refluxed for 6 hours and thenevaporated to dryness and to obtain6-aminomethyl-spiro[3.3]heptane-Z-carboxylic acid hydrochloride (M.P.154-158 C.). This hydrochloride salt is then dissolved in 1 ml. of waterand passed through a column of 20 g. (wet weight) of Dowex-l acetate toobtain the freebase, '6-aminomethylspiro[3.3]heptane 2 carboxylic acid(M.P. 255 260 C.).

EXAMPLE 2 6-aminospiro [3 .3 1heptane-2-carb oxylic acid (A) Methylfi-(N-carbomethoxyamino) -spiro[3.3]heptane-Z-carboxylate: 0.99 g. (5.0mmoles) of methyl 6- carbamoylspiro[3.3lheptane-2-carboxylate fromExample 1(C) is added to a solution of sodium methoxide [prepared from0.25 g. (11.0 mmoles) of sodium in 25 ml. of absolute methanol]. Thesolution is stirred under nitrogen at 0 C. and 0.9 g. (6.0 mmoles) ofbromine is added over a 10 minute period. The reaction mixture is thenrefluxed on a steam bath for 15 minutes, cooled and added to ml. ofwater. This mixture is extracted three times with 50 ml. portions ofether and the combined extracts are dried over magnesium sulfate andevaporated to dryness to obtain methyl 6-('N-carbomethoxyamino)-spiro-[3.3]heptane-2-carboxylate.

(B) 6-aminospiro[3.3]heptane-2-carboxylic acid: A mixture of 0.89 g.(3.92 mmoles) of urethane from step A and 3.0 ml. of cone. hydrochloricacid is refluxed for 8 hours. The reaction mixture is then filteredthrough a sintered glass funnel and evaporated to dryness at 60 70 C. invacuo. To the residue is added 10 ml. of water and the mixture isreevaporated to dryness. This is repeated three more times to obtain6-aminospiro[3.3]heptane-Z-carboxylic acid hydrochloride. This is thendissolved in 2 ml. of water and passed through a column of 30 g. (wetweight) of Dowex I-acetone to obtainG-aminospiro[3.3]heptane-2-carboxylic acid hydrate (M.P. 233- 236 C.)which is then dried over P 0 and paraffin at 100 C./ 10 mm. for 15 hoursto obtain 6-aminospiro- 3. A compound according to claim 1 where R ishy- [3.31heptane-2-carboxylic acid (M.P. 218-220" C.). drogen and R isCH NH thus forming 6-aminomethyl- What is claimed is:spiro[3.31heptane-2-carboxy1ic acid.

1. A compound of the formula:

H H 5 References Cited Liotta et 31.: Chem. Commun. p. 1251, 1969. R000R:

Where: LORRAINE A. WEINBEKGER, Primary Examiner R is hydrogen or loweralkyl; and R. GERSTL, Assistant Examiner R is -CH NH or -NH 10 and itssalts and hydrates. US. Cl. X.R.

2. A compound according to claim 1 where R is hy- 26O 468 G 448 R drogenand R is NH thus forming 6-aminospiro[3.3] heptane-Z-carboxylic acid.

